Aging-related denervation of skeletal muscle results in a significant loss of independence in the elderly population. With age, motor neuron (MN) axons are retracted from the neuromuscular junction (NMJ), leaving behind denervated muscle fibers that cannot be recruited during muscle contraction. This age-related denervation occurs in both humans and animal models, but the underlying mechanisms remain unknown. Recent evidence suggests a new mediator for age-related synapse loss: proteins of the major histocompatibility complex class I (MHCI). MHCI mRNA is constitutively expressed in adult spinal MNs, and MN MHCI levels increase significantly with age. In contrast, in muscles that are resistant to age-related denervation (e.g., the extraocular muscles), MNs consistently express much lower levels of MHCI. These results suggest a model in which MHCI expression contributes to age-related synapse loss at the NMJ. Retraction of MN axons from the NMJ is not limited to aging: it is also a critical aspect of normal development. MN axons retract during the course of postnatal vertebrate development, removing the supernumerary MN inputs that form prenatally. Our preliminary data show that MHCI is expressed during developmental synapse elimination at the NMJ. We also find that developmental synapse elimination is significantly impaired in MHCI-deficient mice. This proposal is guided by the hypothesis that MHCI contributes to removal of MN axons at the NMJ, both during developmental synapse elimination and aging-related synapse loss. The goals of this project are three-fold: 1) Using a MHCI-deficient transgenic mouse model, we will determine if reducing MHCI expression ameliorates aging-related synapse loss at the NMJ. 2) Using RT-PCR and transgenic mouse lines, we will determine if classical MHCIs are required for MN retraction. 3) By expanding our studies to muscles of different fiber type compositions and labeling these fiber types in MHCI- deficient mice, we will determine if MHCI triggers MN retraction specifically at slow twitch muscle fibers. Together, the proposed studies will define the role of MHCI in developmental synapse elimination and aging-associated synapse loss, and could suggest unexpected, immune-based strategies to protect aged muscles from denervation.